Serum Müllerian inhibiting substance levels are lower in premenopausal women with breast precancer and cancer

Müllerian inhibiting substance (MIS), also known as anti-müllerian hormone, is produced by the granulosa cells of growing ovarian follicles. The level of MIS varies throughout a woman's lifetime. MIS is detectable from birth, but increases substantively at puberty. After puberty, MIS slowly decreases until it becomes undetectable after menopause [1]. MIS levels have recently been linked to breast cancer risk [2]. MIS, a member of the transforming growth factor (TGF)-β superfamily, is a 140 kDa dimeric glycoprotein that binds to the MIS type II receptor in breast tissue [3, 4]. MIS inhibits the growth of cultured breast cancer cells through G1 arrest and the induction of apoptosis [5, 6]. An eight-fold increase in the ratio of apoptotic cells in murine mammary tissue was observed after MIS injection [6]. Based on these observations, our hypothesis was that MIS would decrease breast cancer risk in premenopausal women, and that MIS serum levels would be different in women with benign breast disease vs. those with precancer or cancer. The objective of our study was to determine if MIS predicted the benign or malignant nature of a breast lesion requiring biopsy.

Since the primary purpose of MIS in males is the regression of Mullerian structures through the induction of apoptosis [7], it follows that apoptosis induced by cells sensitive to MIS in females may protect against malignant transformation. Breast ductal epithelial cells have MIS receptors which upon stimulation induce apoptosis and inhibit growth [5, 6]. We observed a negative association of MIS concentration with cancerous and precancerous breast lesions in premenopausal women 38-50 years of age. This age range was chosen because breast precancer and cancer is uncommon in women less than 35 years of age [8], and is consistent with the upper age bound used in a prior report on MIS ².

Our observation of lower MIS levels in women with breast precancer and cancer is consistent with both in vitro and animal studies, which suggest that MIS has a cancer preventive effect [3, 5, 6], but is in contrast to an epidemiologic study [2] which suggested that increased MIS levels in healthy women were associated with an increased risk of breast cancer in the future. In that report, the journal editors noted that the association of increased serum MIS concentrations with increased future risk of developing breast cancer is in contrast to previous preclinical findings and what is known about the mechanisms of MIS on breast physiology, which would predict that high MIS concentrations would be associated with lower risk. The author of the epidemiologic study noted that their cohort of case participants had a lower frequency of oral contraceptive use compared to controls, which is at odds with most reports [9]. On the other hand, the OCP use in our precancer and cancer participants was not lower than controls and trended higher in the cancer group, which may in part explain the difference in our results. Additionally, our observations regarding MIS are for current risk, compared to the future risk that was evaluated in the epidemiologic study.

There are limitations to the current study. The first is the limited sample size. A second is that MIS, though associated with disease, was not 100% accurate in differentiating women with precancer or cancer from those without. As such, it is likely that MIS, if validated as associated with current disease in the breast, will need to be combined with other biomarkers for optimal disease prediction. We evaluated whether there was an outlier which might have influenced the association of MIS with disease, but could find none. Our findings provide preliminary evidence for MIS being associated with current breast cancer risk, which should be validated in a larger population.