eNews February 18, 2011

Cholesterol fuels mammary cancer progression and metastasis in mice

Breast cancer is the most common cancer among Western women – five times more prevalent than it is among women in developing countries (Key et al. 2001). In fact, women who migrate from a developing country to the United States increase their breast cancer risk (Shimizu et al. 1991). In 2011, research conducted by Dr. Philippe Frank and colleagues at the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, suggested that increased cholesterol levels accelerate breast cancer development, progression and metastasis (Llaverias et al. 2011).

The PyMT mouse

"The PyMTTg mouse. "Importantly, this mouse tumor model recapitulates human breast cancer progression from early hyperplasia to malignant breast carcinoma" (Llaverias et al. 2011).

As a breast cancer model, Dr. Frank's team used mouse strain FVB/N-Tg(MMTV-PyVT)634Mul/J (002374), hereafter called strain PyMT. Males and females of this strain express the MMTV-driven polyoma virus middle T antigen transgene at high levels in the mammary glands. Females develop palpable mammary tumors by five weeks. Multifocal, highly fibrotic adenocarcinomas involve the entire mammary fat pad and arise in multiple glands. Pulmonary metastases develop in 80-94% of tumor-bearing females. The mammary cancer in these mice closely models human breast cancer progression – from its inception to malignant breast carcinoma and metastases (Guy et al. 1992).

Cholesterol-rich diet exacerbates mammary cancer progression and metastasis

To determine the relationship between a cholesterol-rich diet and mammary cancer progression, Dr. Frank and his team analyzed groups of PyMT females fed either a regular chow or cholesterol-rich diet from age four to 12 weeks. They found that PyMT females fed the cholesterol-rich diet had nearly twice as many palpable tumors as chow-fed controls. Additionally, considerably more of their tumors were poorly differentiated, of a higher histological grade, and exhibited increased mitotic indexes, leukocyte infiltration, vessel density and angiogenesis. The protein expression profiles of the tumors in PyMT females fed a cholesterol-rich diet were also characteristic of advanced mammary cancer. Whereas expression levels of cyclin D1 were high, those of ER alpha and caveolin-1 were low. Finally, these mice had significantly more and larger tumors and tended to develop more lung metastases than controls.

Cholesterol-rich diet accelerates formation of pre-malignant lesions

One of the earliest signs of mammary cancer in PyMT females is pre-malignant lesions, which are present by three weeks of age. Dr. Frank and his team wanted to know if a cholesterol-rich diet would accelerate the development of these lesions. Because three- and four-week old mice obtain most of their nourishment from the mother's milk, the mothers were fed a cholesterol diet during pregnancy (exposing the embryos to high plasma cholesterol levels in utero) and lactation, and the pups had access to the mothers' cholesterol-rich diet until weaning at age three weeks. Frank and his team found that three-week-old female PyMT mice fed a cholesterol-rich diet had 2.5 times more lesions that were 2.5 times larger than in controls. The results were similar in comparably treated four-week old pups, indicating that a cholesterol-rich diet accelerates the development of mammary cancer in these mice.

Cholesterol fuels the progression of mammary cancer

Dr. Frank and his team found several lines of evidence that plasma cholesterol fuels tumor progression in PyMT females. The mean ratio of plasma cholesterol to tumor burden in PyMT females fed a cholesterol-rich diet for eight weeks remained constant. These mice exhibited a nearly two-fold increase in the expression of scavenger receptor class B, member 1 protein (which is responsible for the selective uptake of cholesteryl ester from HDL), their levels of HDL cholesterol were reduced, and, even though they were feeding on a cholesterol-rich diet, the level of total cholesterol in their mammary tumors did not accumulate.

In summary, the research by Dr. Frank and his colleagues was an important contribution to our understanding of the role of cholesterol in breast cancer. As the biochemical pathways involved in cholesterol's role become better understood, they may serve as additional targets in breast cancer therapy.

References

Guy CT, Cardiff RD, Muller, WJ. 1992. Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol Cell Biol 12:954-961.

Key TJ, Verkasalo PK, Banks E. 2001. Epidemiology of breast cancer. Lancet Oncol 2:133-140.

Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG. 2011. Role of cholesterol in the development and progression of breast cancer. Am J Pathol 178:402-412.

Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. 1991. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 63:963-6.